PKCα and PLCγ2 from which downstream mTOR and NFAT signaling is initiated. The upstream Gαi or Gαo signaling suggests the involvement of a G-protein-coupled receptor (GPCR). A candidate GPCR is under study. Syndecan-1 likely serves as a co-receptor. Binding lacritin may improve its GPCR affinity. Lacritin survival signaling is observed when cells are stressed. Lacritin promotes survival and homeostasis by transiently stimulating autophagy. The mechanism appears to involve lacritin stimulated acetylation of the transcription factor FOXO3. Acetylated FOXO3 serves as a ligand for the autophagic mediator ATG101. Lacritin also promotes coupling of FOXO1 (that becomes acetylated with stress) with autophagic mediator ATG7. In the absence of lacritin, no coupling is observed. Thus acetylation alone is likely insufficient for FOXO1-ATG7 ligation, unlike an initial claim. Lacritin also restores oxidative phosphorylation and other metabolic events to rescue cells from stress. Lacritin stimulated secretion of tear proteins lipocalin and lactoferrin from monkey lacrimal acinar cells does not appear to be mediated by Ca2+, unlike the agonist carbachol. When monkey lacrimal acinar cells are stressed with inflammatory cytokines (as occurs in dry eye), carbachol loses its capacity to promote the secretion of lipocalin. However, lacritin stimulates lipocalin secretion even in the presence of stress. Distribution Species Genomic sequencing assembled by Ensembl reveals the existence of putative lacritin orthologues in other species. Comparative genomic alignment suggests that horse lacritin is most similar to human lacritin among all non-primate sequences examined. Moreover, it is detectable in horse tears by immunoblotting or by ELISA. Antibodies directed to the C-, but not N-, terminus of human lacritin are most effective - in keeping with the predicted conservation of the C-terminal amphipathic alpha helix necessary for cell targeting. Tissue Tissue distribution has been examined in humans and monkeys. Lacritin is most highly expressed in the lacrimal gland, including the accessory lacrimal gland of Wolfring. Expression is moderate in salivary glands and slight in mammary (cancer but not or rarely normal), and thyroid glands. The salivary gland expression appears to be attributable to a discrete group of unidentified ductal-like cells. Some lacritin was reported in lung bronchoalveolar lavage and plasma. In lacrimal gland, polarized lacrimal acinar cells appear to be the most prolific lacritin producers, as evidenced by strong staining of secretory granules in keeping with lacritin release after carbachol stimulation. Carbachol-dependent release involves PKC and calcium signaling. Some lacritin is produced by the meibomian gland, and also by epithelial